1. Field of the Invention
The present invention relates to the use of S(+) ketoprofen to elicit an onset-hastened and enhanced antipyretic response in human mammalian organisms in need of such treatment, and to certain pharmaceutical compositions comprising unit dosage effective amounts of S(+) ketoprofen.
2. Description of the Art
Ketoprofen, also known as DL-2-(3-benzoylphenyl)propionic acid, has the structural formula ##STR1## The compound is well-known as a nonsteroidal anti-inflammatory drug having analgesic and antipyretic activity. In the United States, ketoprofen is marketed under the tradename Orudis.RTM.. Other tradenames or codenames include RP 19583, Alrheumat, Alrheumun, Capisten, Fastum, Iso-K, Kefenid, Ketopron, Lertus, Meprofen, Oruvail and Profenid. As Orudis.RTM., the drug is available by prescription in the U.S. as capsules containing 25 mg, 50 mg or 75 mg of ketoprofen, indicated for the acute or long-term treatment of the signs and symptoms of rheumatoid arthritis or osteoarthritis. Orudis.RTM. is recommended at a daily dose of 150 to 300 mg, divided in three or four doses. It is recommended that drug treatment begin at 75 mg three times or 50 mg four times a day. Small people may need smaller doses. Daily dosages should not exceed 300 mg per day. See also Physician's Desk Reference, 41st edition, 1987, publisher Edward R. Barnhart, Medical Economics Company, Inc., Oradell, N.J. 07649, pp. 2179-2181. For mild to moderate pain and dysmenorrhea, a dose of 25 mg to 50 mg every 6 to 8 hours as needed was recently approved by the Food and Drug Administration ("F.D.A.").
As is apparent from its chemical nomenclature, ketoprofen is a racemic mixture. It is only the racemic mixture which has in fact ever been marketed. There have, however, been a few studies of the individual S(+) and R(-) isomers reported in the literature.
The prior art groups the 2-arylpropionic acids together as a class. These possess a chiral center at the carbon atoms alpha to the carboxyl function. According to the prior art, many 2-arylpropionic acids are believed to have a metabolic chiral inversion of their asymmetric center, with partial or complete conversion in nonhuman mammals of the R to the S isomer. The rate and extent of that conversion has been known to vary as noted by Hutt et al, J. Pharm. Pharmacol., 35, 693-704 (1983). This metabolic inversion of the chiral center, with no other covalent change to the drug, is thus far unique to the 2-arylpropionic acids. Cadwell et al., "The Metabolic Inversion and Dispositional Enantioselectivity of the 2-Arylpropionic Acids and their Biological Consequences", Biochem. Pharmacol., 37, 105-114 (1988).
Generally, if an optically active compound has two isomers, there is an argument for resolving what is believed to be the optically active and therapeutically desirable isomer. However, many of the 2-arylpropionic non-steroidal anti-inflammatory drugs (NSAIDs) are unique and run contrary to that argument because of the teachings of the prior art relating to the conversion of the R(-) to the S(+) isomer. Thus, the argument for resolving the 2-arylpropionic acids to improve their clinical effect is not as clear as with other classes of racemic drugs. In many instances, the prior art actually teaches away from such a resolution by leading one of ordinary skill in the art to believe that there would be clinical or near clinical equivalence between the S(+) form and the racemic mixture. That is, the conversion of the R(-) isomer to the S(+) form is believed to progress at such a rate and to such an extent that a substantially equivalent clinical effect would result.
The majority of the prior art was too inconclusive to yield an accurate estimate of the extent of the possible conversion of the R(-) to the S(+) form of ketoprofen in man. Moreover, among the members of that class of NSAID's, comparatively few studies appear to have been conducted on ketoprofen. However, conversion in man would be assumed by one of ordinary skill in the art since in addition to the ketoprofen specific evidence from studies cited in the specification, several members of the 2-arylpropionic acid classes of NSAID's, e.g., ibuprofen, were known to undergo substantial chiral inversion of the R to the S enantiomer in man.
Indeed, Hutt et al concluded that there was no advantage in administering the pure S(+) form of ketoprofen since a rapid in vivo conversion of the R(-) in the racemic mixture to the S(+) form would be expected, based on the fact that ketoprofen has a chiral center and it is known to be incorporated into triglycerides.
Ketoprofen, like fenoprofen, has been reported to be incorporated into triglycerides, and, in addition, a study using [.sup.3 H-.alpha.-methyl] drug in man found increasing quantities of circulating radioactivity due to tritiated water. One means of loss of .sup.3 H from the .alpha.-methyl group would be that proposed for the loss of deuterium from d.sub.4 -ibuprofen during the chiral inversion process. PA1 Interestingly, the R-enantiomer of some of these agents (e.g., ibuprofen, fenoprofen, and benoxaprofen) may undergo a unique in vivo irreversible inversion to the S-enantiomer. This inversion is not a universal occurrence, as, at least in humans, it does not occur to any significant extent with tiaprofenic acid, indoprofen, carprofen, and perhaps ketoprofen.
Hutt et al, "Review - The Metabolic Chiral Inversion of 2-Arylpropionic Acids - A Novel Route with Pharmacological Consequences," J. Pharm. Pharmacol., Vol. 351, pp. 693-674 at 703 (1983). Thus, Hutt et al recognized that evidence existed supporting chiral inverion of the R(-) to the S(+) isomer for ketoprofen.
It has recently been noted that contrary to the expectations of the prior art, there is no conversion of R(-) to S(+) ketoprofen in man.
Jamali et al, "Stereoselective Pharmacokinetics of Flurbiprofen in Humans and Rats," Journal of Pharmaceutical Sciences, Vol. 77, No. 8, pp. 666-69 (August 1988).
In summary, the current state of the art now teaches that there is no conversion of R(-) to S(+) ketoprofen in humans and that the S(+) form is the active enantiomer of ketoprofen. However, there do not appear to be any human experiments on the efficacy of the separate enantiomers reported in the literature. The prior art, moreover, is conspicuously silent in respect to any onset-hastened/enhanced alleviation of mammalian fever utilizing whatever form of the ketoprofen drug species.